US3652571A - Production of 2 4-dihydroxyquinolines - Google Patents

Production of 2 4-dihydroxyquinolines Download PDF

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US3652571A
US3652571A US827020A US3652571DA US3652571A US 3652571 A US3652571 A US 3652571A US 827020 A US827020 A US 827020A US 3652571D A US3652571D A US 3652571DA US 3652571 A US3652571 A US 3652571A
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Hans Juergen Sturm
Helmut Goerth
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4

Definitions

  • This invention relates to the production of 2,4-dihydroxyquinolines.
  • R denotes a hydrogen atom or an electron attracting group
  • R denotes a hydrogen atom or an alkali metal atom
  • X denotes a hydrogen atom, a halogen atom, a nitro group, an alkyl group, an unsubstituted phenyl group or a substituted phenyl group
  • Y denotes a hydrogen or halogen atom or an alkyl group
  • X and Y mayalso be part of a condensed unsaturated ring system are obtained by reacting a compound having the general formula:
  • the alkali metal atom R is potassium or preferably sodium.
  • suitable strong bases are alkali metal alkoxides or alkali metal salts of organic amines.
  • Examples are sodium methoxide, potassium methoxide sodium ethoxide, potassium ethoxide, lithium piperidideor' sodium piperidide.
  • Preferred benzoxazinones-4 have the general formula:
  • R denotes a hydrogen atom or a cyano, acetyl, benzoyl or nitrobenzoyl group
  • X denotes a hydrogen or chlorine atom or a nitro group
  • Y denotes a hydrogen or chlorine atom.
  • the components may be reacted with each other in the ratio 1:1, but a slight excess of the base is advantageous. A large excess is also possible. All compounds conventionally used as solvents are suitable as solvents or diluents for the reaction provided they do not react with the reagents.
  • solvents examples include aliphatic or aromatic hydrocarbons, high boiling ethers, N, N-disubstituted amides or halobenzenes. Specific examples are dimethylcyclohexane, dichlorobenzene, benzonitrile, diethylene glycol dimethyl ether, dimethyl sulfoxide, N-methylpyrrolidone and preferably toluene, xylene or dimethylformamide.
  • R in Formula I does not denote hydrogen, alcohols such as methanol or ethanol may also be used as solvents.
  • An advantageous method of carrying out the new reaction consists for example in placing the benzoxazinone derivative having the Formula II in a solvent or diluent at the reaction temperature or a somewhat lower, temperature, adding the base at such a rate that the reaction does not become too vigorous, keeping the whole for some time at the reaction temperature and then cooling it.
  • the dihydroxyquinoline derivative corresponding to the reaction product is then isolated in the form of the (alkali metal) salt or by acidification as the free acid.
  • the reaction period is from a few minutes to about one hour.
  • the reaction temperature may be from room temperature to about 200 0., preferably from 60 to 150 C. It is an advantage of the new process that the production of the benzoxazinone and the reaction with the base may take place in the same reactor.
  • the invention is illustrated by the following examples.
  • the parts and percentages specified in the following ex- EXAMPLE 1 65 parts of 2-methylbenzoxazinone-4 is heated in 400 parts of xylene at to C. and in about fifteen minutes 25 parts of solid sodium ethylate is added. The mixture is then heated to'130" to C, and kept at this temperature for forty-five minutes, some of the solvent thus being distilled off. The mixture is then cooled to room temperature and the reaction product is suction filtered. The filter cake is added to 1500 parts of water and boiled up so that is passes completely into solution. A pH of from to 6 is set up by adding acid and then the deposited precipitate is suction filtered while hot and dried. 39 parts of 2,4-dihydroxyquinoline is obtained.
  • EXAMPLE 2 65 parts of sodium piperidide is heated to 80 C. in 100 parts of toluene and then a solution of 80 parts of 2- methylbenzoxazinone-4 in 300 parts of toluene is gradually added. The whole is then heated for seventy minutes at boiling point under reflux, after which the solvent is distilled off. The residue is dissolved hot in about 230 parts of dilute caustic soda solution and filtered. The solution is cooled and the reaction product is isolated. The solution is cooled and the reaction product is isolated. 55 parts of 2,4-dihydroxyquinoline is obtained as the sodium salt.
  • EXAMPLE 3 70 parts of anthranilic acid is added in portions to 115 parts of acetic anhydride at from 100 to 120 C. The mixture is boiled and the acetic acid formed is distilled 01f with the excess acetic anhydride. parts of calcined soda and 500 parts of xylene are added to the residue. The whole is heated to 110 to 120 C. and 34 parts of industrial sodium methylate is introduced. The mixture is kept boiling for one hour, some of the liquid thus distilling off. After having been cooled, the whole is suction filtered and the filter cake is dissolved hot in about 1000 parts of water. Another filtration is carried out if necessary and a pH of from 5 to 6 is set up in the solution with hydrochloric acid.
  • the deposited precipitate is suction filtered hot and dried. 32 parts of 2,4 dihydroxyquinoline is obtained. 26 parts of a mixture of acetylanthranilic acid and anthranilic acid can be obtained from the filtrate by setting up a pH of 3, cooling and filtration; this can be used again as starting material.
  • EXAMPLE 4 100 parts of 2 acetonylbenzoxazinone 4 (obtained from anthranilic acid, diketene and acetic anhydride in carbon tetrachloride) is dissolved in 800 parts of methanol. 110 parts of technical sodium methylate solution in methanol is allowed to flow in slowly into the said solution while under reflux. The reaction mixture is kept at boiling temperature for sixty minutes and then the bulk of the solvent is distilled off. The residue is dissolved at the boil in the exact amount of water required and the solution is brought to a pH of from 5 to 6. After cooling, suction filtration and drying, 83 parts of 3 acetyl 2,4 dihydroxyquinoline having a melting point of from 249 to 251 C. is obtained.
  • EXAMPLE 5 12.5 parts of 2 acetonyl 7 nitrobenzoxazinone 4 (obtained from 4-nitroanthranilic acid and an excess of diketene in glacial acetic acid) is dissolved in 250 parts of methyl glycol. 4 parts of sodium methylate is added in portions to the boiling solution. The color of the solution changes from yellow to violet and a short time later to orange, a precipitate being formed. The solution is kept boiling for another three minutes, cooled to room temperature and the precipitate is suction filtered. The filter cake is suspended in water and the mixture adjusted to a pH of from 4 to 5 with hydrochloric acid. After suction filtration, washing until neutral and drying, 9.2 parts of 3 acetyl 7 nitro 2,4 dihydroxyquinoline is obtained having a melting point (recrystallized from methyl glycol) of 288 to 290 C.
  • EXAMPLE 6 18.6 parts of 2 cyanomethylbenzoxazinone 4 (obtained from cyanoacetylanthranilic acid and acetic anhydride) is dissolved in isopropanol and while boiling a solution of 2.5 parts of sodium in isopropanol is added dropwise. The solution is kept boiling for another fifty minutes and the bulk of the solvent is then distilled 01f. The residue is taken up in 1 part by volume of boiling water, the whole passing into solution when a few drops of caustic soda solution is added. The mixture is acidified with dilute hydrochloric acid until the first persisting precipitate occurs. After cooling, suction filtration and drying, 14.2 parts of 3 cyano 2,4 dihydroxyquinoline having a melting point (after reprecipitation while hot) of 292 to 294 C. is obtained.
  • EXAMPLE 7 13.6 parts of 6,8 dichloro 2 acetonyl benzoxazinone-4 (prepared by reacting 3,6 dichloroanthranilic acid With diketene in dry dichlorobenzene and cyclizing the product with acetic anhydride) is stirred in parts of methanol and at 50 to 60 C. a solution of 4 parts of sodium methylate in methanol is dripped in. The Whole is stirred for 60 minutes at 50 to 60 C. and then approx. 200 parts of water is added. The mixture is adjusted at approx. 40 to 50 C. to pH 3 to 4 with hydrochloric acid, stirred for 30 minutes, allowed to cool to room temperature and filtered.
  • 6,8 dichloro 2 acetonyl benzoxazinone-4 prepared by reacting 3,6 dichloroanthranilic acid With diketene in dry dichlorobenzene and cyclizing the product with acetic anhydride
  • a base selected from the class consisting of alkali metal alkoxides and alkali metal salts of organic amines.
  • a strong base selected from the class con- References Cited sisting of sodium methoxide, potassium methoxide, 50- UNITED STATES PATENTS dium ethoxide, potassium ethoxide and sodium piperi'dide. 3 328 397 6/1967 Ben 3.
  • a process as claimed m clalm 1 w ereln the reac US Cl- XRI tion is carried out at a temperature of from 60 C. to r 150 C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

PRODUCTION OF 2,4-DIHYDROXYQUINOLINES OR DERIVATIVES THEREOF STARTING FROM BENZOXAZINONES AND USING A STRONG BASE.

Description

United States Patent US. "Cl. 260-289 4 Claims ABSTRACT on THE DISCLOSURE Production of. 2,4;dihydroxyquinblines or derivatives thereof starting from. benzoxazin ones and using a strong base. l
This invention relates to the production of 2,4-dihydroxyquinolines.
We have found that compounds having the general formula:
(I) where R denotes a hydrogen atom or an electron attracting group -R denotes a hydrogen atom or an alkali metal atom, X denotes a hydrogen atom, a halogen atom, a nitro group, an alkyl group, an unsubstituted phenyl group or a substituted phenyl group, and Y denotes a hydrogen or halogen atom or an alkyl group, and X and Y mayalso be part of a condensed unsaturated ring system are obtained by reacting a compound having the general formula:
hydrogen, chlorine and-.nitro.--The. substituents X and Y, are preferably in the 6-, 7-. or 8-position ofthe compoundsv ofFormula I. t a a I Groups LR whichattractelectronsare, for example acyl groups such as acetyl, propionyl, benzoyl or ;nitro benzoyl or nitro, sulfonyl alkylsulfonyl or cyano groups. Apart from hydrogen, it is preferred to use as groups R acetyl, cyano, benzoyl and substituted benzoyl. Examples of alkylsulfonyl groups are methylsulfonyl and ethylsulfonyl.
The alkali metal atom R is potassium or preferably sodium. v 1
Examples of suitable strong bases are alkali metal alkoxides or alkali metal salts of organic amines. Examples are sodium methoxide, potassium methoxide sodium ethoxide, potassium ethoxide, lithium piperidideor' sodium piperidide.
Some of the compounds having the Formula II (benzamples relate to weight.
3,652,571 Patented Mar. 28, 1972 oxazinones-4) to be used as starting materials are known from the literature. They may be prepared by acylation of o-aminoarylcarboxylic acids and subsequent elimination of water in an acid medium.
Preferred benzoxazinones-4 have the general formula:
where R denotes a hydrogen atom or a cyano, acetyl, benzoyl or nitrobenzoyl group, X denotes a hydrogen or chlorine atom or a nitro group and Y denotes a hydrogen or chlorine atom.
In the reaction of the benzoxazinones-4 with strong bases according to this invention, the components may be reacted with each other in the ratio 1:1, but a slight excess of the base is advantageous. A large excess is also possible. All compounds conventionally used as solvents are suitable as solvents or diluents for the reaction provided they do not react with the reagents.
- Examples of suitable solvents are aliphatic or aromatic hydrocarbons, high boiling ethers, N, N-disubstituted amides or halobenzenes. Specific examples are dimethylcyclohexane, dichlorobenzene, benzonitrile, diethylene glycol dimethyl ether, dimethyl sulfoxide, N-methylpyrrolidone and preferably toluene, xylene or dimethylformamide. When R in Formula I does not denote hydrogen, alcohols such as methanol or ethanol may also be used as solvents.
An advantageous method of carrying out the new reaction consists for example in placing the benzoxazinone derivative having the Formula II in a solvent or diluent at the reaction temperature or a somewhat lower, temperature, adding the base at such a rate that the reaction does not become too vigorous, keeping the whole for some time at the reaction temperature and then cooling it. The dihydroxyquinoline derivative corresponding to the reaction product is then isolated in the form of the (alkali metal) salt or by acidification as the free acid. The reaction period is from a few minutes to about one hour. The reaction temperature may be from room temperature to about 200 0., preferably from 60 to 150 C. It is an advantage of the new process that the production of the benzoxazinone and the reaction with the base may take place in the same reactor.
As compared with prior art methods for making 2,4- dihydroxyquinoline reaction of acetylanthranilic acid with sodamide in a melt of sodium hydroxide and potassium hydroxide at temperatures of from 150 to 180 C., v. Bios, 1153, 323) or 3-acetyl-Z,4-dihydroxyquinoline (reaction of methyl acetoacetylanthranilate with metallic sodium in toluene at refluxing temperature, see J. Chem. Soc. (London), 1954, 850), the new process is "more widelyapplicable and uses substantially milder reaction conditions.
The invention is illustrated by the following examples. The parts and percentages specified in the following ex- EXAMPLE 1 65 parts of 2-methylbenzoxazinone-4 is heated in 400 parts of xylene at to C. and in about fifteen minutes 25 parts of solid sodium ethylate is added. The mixture is then heated to'130" to C, and kept at this temperature for forty-five minutes, some of the solvent thus being distilled off. The mixture is then cooled to room temperature and the reaction product is suction filtered. The filter cake is added to 1500 parts of water and boiled up so that is passes completely into solution. A pH of from to 6 is set up by adding acid and then the deposited precipitate is suction filtered while hot and dried. 39 parts of 2,4-dihydroxyquinoline is obtained.
EXAMPLE 2 65 parts of sodium piperidide is heated to 80 C. in 100 parts of toluene and then a solution of 80 parts of 2- methylbenzoxazinone-4 in 300 parts of toluene is gradually added. The whole is then heated for seventy minutes at boiling point under reflux, after which the solvent is distilled off. The residue is dissolved hot in about 230 parts of dilute caustic soda solution and filtered. The solution is cooled and the reaction product is isolated. The solution is cooled and the reaction product is isolated. 55 parts of 2,4-dihydroxyquinoline is obtained as the sodium salt.
EXAMPLE 3 70 parts of anthranilic acid is added in portions to 115 parts of acetic anhydride at from 100 to 120 C. The mixture is boiled and the acetic acid formed is distilled 01f with the excess acetic anhydride. parts of calcined soda and 500 parts of xylene are added to the residue. The whole is heated to 110 to 120 C. and 34 parts of industrial sodium methylate is introduced. The mixture is kept boiling for one hour, some of the liquid thus distilling off. After having been cooled, the whole is suction filtered and the filter cake is dissolved hot in about 1000 parts of water. Another filtration is carried out if necessary and a pH of from 5 to 6 is set up in the solution with hydrochloric acid. The deposited precipitate is suction filtered hot and dried. 32 parts of 2,4 dihydroxyquinoline is obtained. 26 parts of a mixture of acetylanthranilic acid and anthranilic acid can be obtained from the filtrate by setting up a pH of 3, cooling and filtration; this can be used again as starting material.
EXAMPLE 4 100 parts of 2 acetonylbenzoxazinone 4 (obtained from anthranilic acid, diketene and acetic anhydride in carbon tetrachloride) is dissolved in 800 parts of methanol. 110 parts of technical sodium methylate solution in methanol is allowed to flow in slowly into the said solution while under reflux. The reaction mixture is kept at boiling temperature for sixty minutes and then the bulk of the solvent is distilled off. The residue is dissolved at the boil in the exact amount of water required and the solution is brought to a pH of from 5 to 6. After cooling, suction filtration and drying, 83 parts of 3 acetyl 2,4 dihydroxyquinoline having a melting point of from 249 to 251 C. is obtained.
EXAMPLE 5 12.5 parts of 2 acetonyl 7 nitrobenzoxazinone 4 (obtained from 4-nitroanthranilic acid and an excess of diketene in glacial acetic acid) is dissolved in 250 parts of methyl glycol. 4 parts of sodium methylate is added in portions to the boiling solution. The color of the solution changes from yellow to violet and a short time later to orange, a precipitate being formed. The solution is kept boiling for another three minutes, cooled to room temperature and the precipitate is suction filtered. The filter cake is suspended in water and the mixture adjusted to a pH of from 4 to 5 with hydrochloric acid. After suction filtration, washing until neutral and drying, 9.2 parts of 3 acetyl 7 nitro 2,4 dihydroxyquinoline is obtained having a melting point (recrystallized from methyl glycol) of 288 to 290 C.
EXAMPLE 6 18.6 parts of 2 cyanomethylbenzoxazinone 4 (obtained from cyanoacetylanthranilic acid and acetic anhydride) is dissolved in isopropanol and while boiling a solution of 2.5 parts of sodium in isopropanol is added dropwise. The solution is kept boiling for another fifty minutes and the bulk of the solvent is then distilled 01f. The residue is taken up in 1 part by volume of boiling water, the whole passing into solution when a few drops of caustic soda solution is added. The mixture is acidified with dilute hydrochloric acid until the first persisting precipitate occurs. After cooling, suction filtration and drying, 14.2 parts of 3 cyano 2,4 dihydroxyquinoline having a melting point (after reprecipitation while hot) of 292 to 294 C. is obtained.
EXAMPLE 7 13.6 parts of 6,8 dichloro 2 acetonyl benzoxazinone-4 (prepared by reacting 3,6 dichloroanthranilic acid With diketene in dry dichlorobenzene and cyclizing the product with acetic anhydride) is stirred in parts of methanol and at 50 to 60 C. a solution of 4 parts of sodium methylate in methanol is dripped in. The Whole is stirred for 60 minutes at 50 to 60 C. and then approx. 200 parts of water is added. The mixture is adjusted at approx. 40 to 50 C. to pH 3 to 4 with hydrochloric acid, stirred for 30 minutes, allowed to cool to room temperature and filtered. The filtrate is washed successively with water, methanol, acetone and ether and then dried. 11.75 parts of 6,8 dichloro 2,4 dihydroxy-3- acetylquinoline is obtained; M.P. (from dimethylformamide) 303 to 306 C.
We claim:
1. A process for the production of a compound of the formula wherein R is hydrogen, nitro, alkylsulfonyl, cyano, acetyl, proiCIIzR N where R, X and Y have the meanings given above,
with a base selected from the class consisting of alkali metal alkoxides and alkali metal salts of organic amines.
2. A process as claimed in claim 1, wherein a compound having the formula wherein R is cyano, acetyl, benzoyl or nitrobenzoyl, X is hydrogen, chlorine or nitro and Y is hydrogen or chlorine,
6 is reacted with a strong base selected from the class con- References Cited sisting of sodium methoxide, potassium methoxide, 50- UNITED STATES PATENTS dium ethoxide, potassium ethoxide and sodium piperi'dide. 3 328 397 6/1967 Ben 3. A process as clalmed in claim 1 wherein the reac- 5 3,450,700 6/1969 salaigh 260 244 tion is carried out at a temperature of from room temperature up to about 200 C. DONALD G. DAUS, Primary Examiner h 4 A process as claimed m clalm 1 w ereln the reac US Cl- XRI tion is carried out at a temperature of from 60 C. to r 150 C. 10 260244, 283 SY, 283 ON mg I v UNITED STATES PATE T OFFICE CERTIFICATE OF'CORRECTION Patent No. I 5,652,57 Dated March 28, 19 72 lgventoflg) Hahs-JUergen Sturm' and Helmut Goerth Itiscertified that error appears in the above-identified patent and that saidv Letters Patent are hereby corrected as shown below:
Column 1, line 3, "Grunstadt should read Gruenstadt line Bl, group R' should read 1 group )R Column 2, line 66; "ethylate" should read methylate Column 5, line 1, "is" should read H 11:
Column 5, lines 14 to l5, cancel "The solution is cooled and the reaction product is isolated Signedand sealed this 5th day of December 1972.-
(SEAL) Attest:
EDWARD M.FLETCH1:;R,JR, ROBERT GOTTSCHALK Attesting Officer] I Commissioner of Patents
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4302460A (en) * 1979-03-27 1981-11-24 The Boots Company Limited 4-Quinolinones having antihypertensive activity
US5622965A (en) * 1993-03-12 1997-04-22 State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon, Eugene Oregon 4-hydroxy-3-nitro-1,2-dihydroquinolin-2-ones and the use thereof as excitatory amino acid and glycine receptor antagonists
US5831091A (en) * 1995-11-17 1998-11-03 Tanabe Seiyaku Co., Ltd. Process for preparing acetoxyazetidinone derivative and intermediate thereof

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4065457A (en) * 1973-05-19 1977-12-27 Beecham Group Limited 4-Hydroxy-3-nitro-carbostyril compounds
GB1489332A (en) * 1973-10-11 1977-10-19 Beecham Group Ltd Reduced bicyclic pyridone derivatives
US4006237A (en) 1973-10-11 1977-02-01 Beecham Group Limited Tetrahydrocarbostyril derivatives for the prophylaxis of asthma, hayfever and rhinitis
DE2631317A1 (en) * 1975-07-23 1977-02-17 Sandoz Ag ORGANIC COMPOUNDS, THEIR USE AND MANUFACTURING

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4302460A (en) * 1979-03-27 1981-11-24 The Boots Company Limited 4-Quinolinones having antihypertensive activity
US5622965A (en) * 1993-03-12 1997-04-22 State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon, Eugene Oregon 4-hydroxy-3-nitro-1,2-dihydroquinolin-2-ones and the use thereof as excitatory amino acid and glycine receptor antagonists
US5831091A (en) * 1995-11-17 1998-11-03 Tanabe Seiyaku Co., Ltd. Process for preparing acetoxyazetidinone derivative and intermediate thereof

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CH511851A (en) 1971-08-31
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